PA28γ promotes the malignant progression of tumor by elevating mitochondrial function via C1QBP

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Proteasome activator 28γ (PA28γ) is implicated in tumor progression, but its regulatory mechanisms and specific roles remain unclear.
• Understanding PA28γ's interactions is crucial for developing targeted cancer therapies, particularly in oral squamous cell carcinoma (OSCC).

Purpose of the Study:

• To elucidate the interaction between PA28γ and complement 1q binding protein (C1QBP) in OSCC.
• To investigate the functional consequences of this interaction on mitochondrial metabolism and tumor progression.
• To assess the clinical relevance and prognostic value of PA28γ and C1QBP co-expression in OSCC.

Main Methods:

• Co-immunoprecipitation (Co-IP) and proximity ligation assays (PLA) to confirm PA28γ-C1QBP interaction.
• AlphaFold 3-based molecular docking and truncation constructs to map interaction domains.
• Mitochondrial function assays (OPA1, MFN1/2, OXPHOS, ATP, ROS) and in vitro/in vivo tumor growth models.
• Analysis of clinical OSCC cohorts to correlate protein expression with prognosis.

Main Results:

• PA28γ directly interacts with C1QBP, primarily through the C1QBP N-terminus, stabilizing C1QBP protein levels in OSCC.
• The PA28γ-C1QBP complex localizes to mitochondria, enhancing mitochondrial fusion, oxidative phosphorylation (OXPHOS), ATP production, and ROS generation.
• PA28γ-driven OSCC cell migration, invasion, and proliferation are dependent on C1QBP.
• PA28γ overexpression increases tumor growth, ATP, and ROS in vivo, while PA28γ deficiency suppresses these effects.
• High co-expression of PA28γ and C1QBP correlates with poor prognosis in OSCC patients.

Conclusions:

• PA28γ stabilizes C1QBP via N-terminal interaction, promoting mitochondrial metabolism and driving OSCC progression.
• The PA28γ-C1QBP axis represents a significant factor in oral carcinogenesis and metastatic potential.
• Targeting the PA28γ-C1QBP interaction offers a promising therapeutic strategy for OSCC.